Accelerating antibody discovery using transgenic animals overexpressing the neonatal Fc receptor as a result of augmented humoral immunity

Abstract

In recent years, there has been an increasing demand for the development of faster and more efficient technologies for the generation of monoclonal antibodies against challenging targets that are weakly immunogenic or available only in limited amounts. Typical classes of such targets are cell surface antigens such as G-protein related receptors (GPCRs) or ion channels. We have developed transgenic (Tg) mice and rabbits that overexpress the neonatal Fc receptor (FcRn), resulting in an augmented humoral immune response even if challenging antigens are used for immunization. The impressively enhanced FcRn-mediated immune reactions are characterized by improved IgG protection and enhanced antigen presentation leading to greater number of antigen-specific T-helper and B-cell activation in lymphoid organs. Notably, these animals do not show any sign of autoimmunity and can be efficiently bred. FcRn overexpression thus leads to a number of practical benefits for improved generation of monoclonal and polyclonal antibodies against multiple antigens, including weakly immunogenic epitopes or tiny amounts of proteins. This review summarizes our current understanding about the mechanisms by which FcRn overexpression leads to such a significantly enhanced humoral immune response.

ORAI2 modulates store-operated calcium entry and T cell-mediated immunity

“…Surface expression of human ORAI1 in fibroblasts was detected using two different custom-made anti-human ORAI1 monoclonal antibodies, which both recognize the second extracellular loop of hORAI1. Clone 29A2 is a mouse anti-human ORAI1 mAb (IgG1) that was generated with an ovalbumin conjugated peptide corresponding to amino acids 196 to 234 of human ORA1 using mice that overexpress the neonatal Fc receptor (FcRn) and have augmented immune response due to the role of FcRn in antigen presentation62. Immune sera and hybridoma supernatants were tested using human ORAI1 transfected and parenteral NIH-3T3 cells with flow cytometry analyses.…”

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

“…Initially used as naïve hosts for the production of murine monoclonal antibodies, today transgenic mice are capable of generating fully human antibodies (5–9). Mice provide an excellent preclinical platform to model a wide spectrum of human diseases and investigate diagnostic and therapeutic strategies (10–13).…”

Characterization of the interactions of rabbit neonatal Fc receptor (FcRn) with rabbit and human IgG isotypes

“…The neonatal Fc receptor, FcRn is a heterodimer consisting of an MHC-I like α-chain and β 2 -microglobulin (β2m) [ 1 ]. FcRn plays an important role in the transcytosis of maternal IgG to the fetus and in maintaining IgG and albumin homeostasis in adult [ 2 ], as well as in antigen presentation by professional Ag presenting cells in case of Ag-IgG immune complexes [ 3 – 5 ].…”